CN109562179A

CN109562179A - The new application of the bis- -2- mercaptoethyl isophtalamides of N, N-

Info

Publication number: CN109562179A
Application number: CN201780046065.1A
Authority: CN
Inventors: 博伊德·尤金·哈利; 雷格纳·阿克塞尔·西奥多·克林伯格
Original assignee: Aime Rami De Ltd
Current assignee: Aime Rami De Ltd
Priority date: 2016-08-05
Filing date: 2017-08-04
Publication date: 2019-04-02
Also published as: EA201990443A1; MD3493849T2; AU2017305661B2; UA125394C2; EP4029497A1; ES2907838T3; IL264538B2; MA45855B1; SG11201900565RA; JP2019524782A; ZA201900594B; MX2019000978A; KR20190035724A; AU2017305661A1; MA45855A; PT3493849T; CL2019000229A1; IL264538A; WO2018025049A1; LT3493849T

Abstract

Provide the compound N for treating or preventing acetaminophen toxicity, the bis- -2- mercaptoethyl isophtalamides (NBMI) of N- or its pharmaceutically acceptable salt and/or derivative.This kind of compound can be particularly useful for the treatment of or prevent acute hepatic failure relevant to acetaminophen toxicity.

Description

The new application of the bis- -2- mercaptoethyl isophtalamides of N, N-

Technical field

The present invention relates to compound N, bis- -2- mercaptoethyl isophtalamides (NBMI) of N- and its pharmaceutically acceptable The new medical application of salt and/or derivative.Particularly, the present invention relates to this compounds for treating or preventing paracetamol The purposes of toxic effect, the toxic effect may due to paracetamol over administration toxic effect and occur.More particularly, The present invention can be related to the treatment or prevention of the acute hepatic failure occurred due to acetaminophen toxicity.

Background technique

It lists or discusses obviously to regard as in disclosed file before in the present specification and recognize that the file is existing A part of state of the art either common knowledge.

The hepatopathy as caused by liver damage represents serious and often fatal situation.Acute hepatic failure (ALF) is The hepatopathy of most serious has the very high death rate in patients.ALF have many potential causes of disease, including liver disease progression (such as Virus hepatitis, alcoholic liver disease and non-alcoholic fatty liver disease) and drug toxic effect.

Hepatic lesion may be caused so as to cause in those of ALF drug known, the toxicity special hazard of paracetamol, It is damaged rapidly especially because it may result in hepatic tissue, often causes the hepatic lesion of unrepairable, and therefore caused not Reversible hepatic failure.

Paracetamol (also referred to paracetamol) is a kind of widely used effective mild pain to moderate pain Antalgica.It is unexpected but since it is exactly high toxicity under the dosage of only slightly higher than dose therapeutically effective Paracetamol poisoning be a serious risk.Further, since commonly known paracetamol can have wound in excessively application Evil effect, therefore self injury is used as in those of introgression people by the intentional paracetamol poisoning of over administration A kind of mode.For these reasons, paracetamol over administration is the poisoning of the approval drug of most common form, is only existed every year US and European will cause the first aid event more than 100,000.

After application, paracetamol is metabolized as toxic intermediate N- acetyl group-p- benzoquinone imine (NAPQI) in liver, It in conjunction with endogenous antioxidant glutathione under normal circumstances by detoxifying, consequently as atoxic cysteinyl Paracetamol discharge.But when being under pressure, such as gluathione in the case where paracetamol over administration, in liver Peptide storage is consumed, and is caused oxidative stress and is formed NAPQI- albumen addition product, can then cause hepatic lesion rapidly.Tight In weight situation, this toxic effect can cause ALF, if may cause death without treatment.

The standard care of acetaminophen toxicity is the n-acetylcysteine (NAC) of administered with high dose in a long time. NAC is a kind of analog of cysteine, it is a kind of precursor of glutathione, therefore it is believed that can supplement the gluathione in liver Peptide storage, to restore its protective effect.When 8 of the paracetamol in intake toxicity dose is small when interior application, NAC can be effective The toxicity for treating paracetamol.But if applied after intake paracetamol 8 hours or more, the validity meeting of NAC treatment Weaken rapidly, this is because glutathione level at this moment is decreased too many (approximately less than the 70% of normal level), it cannot In conjunction with all NAPQI metabolins, this can cause the damage of liver.Although NAC itself can be tied in vitro with NAPQI really It closes, but NAC cannot prevent to be poisoned in vivo.

Therefore for developing new effective substitution treatment for treating and preventing the hepatic lesion as caused by acetaminophen toxicity There is significant clinically unsatisfied demand in method.

Bis- -2- mercaptoethyl the isophtalamides (NBMI) of N, N- are first with US patent No. US6,586,600B2 authorization Patent application in disclose.It has carried out public affairs as the purposes of dietary supplements in U.S. Patent application 2010/0227812 It opens, and also knows that it is the chelating agent of the heavy metal as mercury, chromium and lead.The analog of NBMI also exists among other It is carried out in the United States Patent (USP) US8,426,368B2 and international patent application WO2011/038385 and WO2012/121798 of authorization It is open.

But there is no with NBMI or derivatives thereof for treating or preventing the hepatic lesion as caused by acetaminophen toxicity The relevant introduction of potential use or suggestion.

Summary of the invention

We have now surprisingly found that liver damage can be prevented or reduce by applying NBMI after paracetamol over administration Evil, to provide the effective ways for treating or preventing acetaminophen toxicity.Therefore NBMI show be directed to acetaminophen toxicity and with The improvement therapy of the relevant acute hepatic failure of acetaminophen toxicity has very big prospect.

New method and medical application

According to the first aspect of the invention, the compound N for treating or preventing acetaminophen toxicity is provided, N- is bis-- 2- mercaptoethyl isophtalamide (NBMI) or its pharmaceutically acceptable salt and/or derivative.

Unless otherwise defined, NBMI and its pharmaceutically acceptable salt and/or derivative can herein referred to as " originally Invention compound ".

Of the invention alternative in a first aspect, provide compound N, the bis- -2- mercaptoethyl isophtalamides of N- or Its pharmaceutically acceptable salt and/or derivative are used to manufacture the purposes for the drug for treating or preventing acetaminophen toxicity.

Of the invention further alternative in a first aspect, providing a kind of for treating or preventing acetaminophen toxicity Method, the method include to apply a effective amount of N to patient with this need (patients of i.e. this treatment or prevention), and N- is bis-- 2- mercaptoethyl isophtalamide or its pharmaceutically acceptable salt and/or derivative.

Unless otherwise noted, otherwise all scientific and technical terminologies used herein all have and common skill of the art Art personnel are generally understood identical meaning.

Unless context is it is further noted that otherwise the special characteristic and embodiment described in terms of the present invention is given should be seen Work discloses together with any and all other special characteristics and embodiment of this aspect of the present invention.

In order to avoid query, compound N BMI as described herein can also pass through trade nameOr pass through the world Nonproprietary name (INN) Emeramide is referred to.The structure of the compound (salt-independent shape) passes through following presentation.

If the pharmaceutically acceptable salt referred in the scope of the invention includes acid-addition salts and base addition salts.This salt can lead to It crosses and is conventionally formed；For example, by by the compounds of this invention of free acid or free alkali form and monovalent or more equivalents Acid or alkali appropriate react to be formed, and optionally in a solvent or in the medium that the salt will not dissolve, then use standard skill Art (such as under reduced pressure, by being freeze-dried or passing through filtering) removes the solvent or the medium.It can also be by by salt shape The counter ion of the compounds of this invention of formula exchanges (such as using suitable amberlite Ester exchange) system with another counter ion Standby salt.

The specific acid-addition salts that can be mentioned that include that carboxylate is (such as formates, acetate, trifluoroacetate, propionate, different Butyrate, enanthate, caprate, caprate, caprylate, stearate, acrylates, caproate, propiolate, ascorbic acid Salt, citrate, glucuronate, glutamate, glycollate, alpha-hydroxybutyric acid salt, lactate, tartrate, phenyl second Hydrochlorate, mandelate, phenylpropionic acid salt, phenylbutyrate, benzoate, chloro benzoate, methyl benzoic acid salt, hydroxy benzenes first Hydrochlorate, methoxy benzoic acid salt, dinitro-benzoate, o- acetoxy-benzoic salt, salicylate, nicotinate, isonicotinic acid Salt, cinnamate, oxalates, malonate, succinate, suberate, sebacate, fumarate, malate, Malaysia Hydrochlorate, hydroxymaleic acid salt, hippurate, phthalate or terephthalate), haloid (such as villaumite, bromide or Salt compounded of iodine), sulfonate (such as benzene sulfonate, toluene fulfonate, bromobenzenesulfonate or closilate, xylenesulfonate, methylsulphur Hydrochlorate, esilate, propane sulfonic acid salt, hydroxy-ethanesulfonate salt, 1- or 2- naphthalene-sulfonate or 1,5- napadisilate) or sulfuric acid Salt, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, dibasic alkaliine, dihydric phosphate, metaphosphoric acid Salt, pyrophosphate or nitrate etc..

The specific base addition salts that can be mentioned that include and alkali metal (such as Na salt and K salt), alkaline-earth metal (such as Mg salt and Ca Salt), the salt that is formed of organic base and inorganic base (such as aluminium hydroxide).More particularly, the base addition salts that can be mentioned that include Mg salt, Ca Salt and most special K salt and Na salt.

The specific pharmaceutically acceptable salt (especially when forming the salt of NBMI) that can be mentioned that includes base addition salts, such as The salt (such as the salt formed with Na or K) formed with alkali metal.

It should be understood to the one skilled in the art that refer to the pharmaceutically acceptable derivates of NBMI include according to those skilled in the art The step of knowing (such as by the way that one or more-NH- group and/or-SH is group modified) forms NBMI derivatization Compound.For example, referring to that this derivative may include by being alkylated (such as formation-NR¹Group, wherein R¹It indicates C_1-3Alkyl is optionally replaced by one or more fluorine, such as wherein R¹Indicate methyl) by-NH- group derivatization, and/ Or by being alkylated (such as formation-SR²Group, wherein R²Indicate C_1-3Alkyl is optionally taken by one or more fluorine Generation, such as wherein R²Indicate methyl) or be esterified (such as formation-SC (O) R³Group, wherein R³Indicate C_1-3Alkyl, optionally Ground is replaced by one or more fluorine, such as wherein R³Indicate methyl, or by being capable of forming the pharmaceutically acceptable of this thioesters Compound (such as pharmaceutically acceptable carboxylic acid or ester) another group that generates of reaction) by-SH group derivatization.

The specific pharmaceutically acceptable derivates for the NBMI that can be mentioned that include glutathione, cysteine, α dihydro sulphur The thio adenosine of octanoic acid, cystine, thiophosphate, 5'-, L- homocysteine, coacetylase, 2 mercapto ethanol and dithiothreitol (DTT) Disulphide bridges connect addition product.This derivative can by with (for example) described in US patent application 2011/0237776 it is similar Step preparation, content are incorporated herein by reference.

In order to avoid query, " bis- -2- mercaptoethyl isophtalamides (NBMI) of N, N- or its is pharmaceutically acceptable are referred to Salt and/or derivative " show that NBMI can be with its pharmaceutically acceptable salt, its pharmaceutically acceptable derivates or its medicine The form of the pharmaceutically acceptable salt of acceptable derivates exists on.

The special compound of the invention that can be mentioned that includes NBMI and its pharmaceutically acceptable salt.

The more particularly compound of the invention that can be mentioned that includes NBMI.

In order to avoid query, the compounds of this invention can be used as solid presence, therefore the scope of the present invention include its institute whether there is or not Amorphous form, crystal form and partial crystals form.The compounds of this invention in the form of crystal form and partial crystals existing for In the case of, this form may include solvate comprising within the scope of the invention.The compound of the present invention also may be present in In solution.

The invention also includes the compounds of this invention of isotope labelling, they are identical, but due to one or more Atom that atom is had the atomic weight or mass number different from atomic weight usually existing in nature or mass number (or it is natural Highest one kind of content in boundary) substitution the fact that.All isotopes of any specific atoms as noted herein or element It is taken into account in the range of the compounds of this invention.Therefore, refer to that the compound of the present invention further includes deuterated compound, i.e., wherein One or more hydrogen atoms are substituted by hydrogen isotope deuterium.

It should be understood to the one skilled in the art that " treatment (treatment) " of a kind of referenced herein particular condition is (or similar Ground refers to " treatment (the treating) " situation) general sense of taking it in drug field.Particularly, which can relate to And reduce the severity of one or more clinical symptoms relevant to the situation.

It should be understood to the one skilled in the art that " prevention (prevention) " of a kind of referenced herein particular condition is (and similar Ground refers to " prevention (the preventing) " situation) take its general sense in the art.Particularly, these terms can It is related to reducing and generates conditions associated or (such as reduction when compared with baseline level with the conditions associated relevant symptom a possibility that At least 10%, such as at least 20% is reduced, or more particularly, it reduces at least 30%).Similarly, term " prevention (preventing) " it also may be referred to conditions associated " prevention (prophylaxis) ", vice versa.

For example, working as about acetaminophen toxicity in use, referring to that " prevention (prevention) " can refer to reduces patient's meeting A possibility that being subjected to toxic effect (such as hepatic lesion, including ALF) of paracetamol.Similarly, " treatment is referred to (treating) " it can refer to the severity for reducing the toxic effect (such as hepatic lesion, including ALF) of paracetamol.

As used herein, refer to that " patient " refers to the object of treated work, including mammal (the especially mankind) Patient, this " patient " also may be referred to " object ", and vice versa.Refer to that " patient " (therefore equally referring to " object ") should also be seen Work refers to that the individual for not showing conditions associated symptom, preventative (preventative) that the compounds of this invention can be used as it are arranged It applies or preventative (prophylactic) measure (as difined above).

In order to avoid query, it may also include when referring to patient and refer to animal, such as nonmammalian (such as bird), especially Mammal (such as cat, dog, rabbit, mouse, horse, goat, pig, goat, ox, primate etc.).

As used herein, term " effective quantity " refers to can assign desired therapeutic effect (i.e. as herein for treatment object The desired treatment or prevention) compound amount.The effect can be objectively (can be by some tests or mark Note measurement) or it is subjective (i.e. object provides a kind of instruction and/or experiences a kind of effect).

It should be understood to the one skilled in the art that acetaminophen toxicity (and similar paracetamol poisoning) refers to a kind of situation, it is special Sign is the clinical effect being subjected to after the paracetamol for applying toxicity dose (i.e. excessive).Hot breath is flutterred as such, treating or preventing Pain toxicity also may be referred to that paracetamol over administration (its can do it on purpose or unintentionally), (it can refer to paracetamol abuse The intentional over administration of paracetamol), the treatment of paracetamol poisoning (its can do it on purpose or unintentionally) etc..

Particularly, can be higher than by the level of Liver enzyme alanine aminotransferase (ALT) and/or aminopherase (AST) 1000 units/L shows the toxicity of paracetamol.Its feature can be necrosis of liver cells (damaging caused by liver cell), Its feature can then be the acute hepatic failure (ALF) under liver function is impaired and serious conditions.The feature of this effect is starting When (first 24 hours after paracetamol over administration) can be the symptom as nausea and vomiting, followed by under right rib The breaking-out of pain and tenderness shows that hepatic lesion starts to break out.

It should be understood to the one skilled in the art that the amount for constituting acetaminophen toxicity dosage is height change, and may depend on several Factor, such as weight, age and the general health of patient.The toxicity dose of paracetamol can pass through acute use excess (i.e. due to the toxicity amount applied in any one dosage and the over administration occurred) or chronic administration are (i.e. due to several dosage Cumulative function and the over administration occurred) occur.In short, the day of greater than about 10 to 12g (or about 150mg/kg weight) is accumulative The single dosage of dosage and about 4.5 to 6g (or 75mg/kg weight) is generally acknowledged to be likely to cause to be poisoned.

In addition, it should be understood to the one skilled in the art that acetaminophen toxicity (such as is being subjected to liver function to the more sensitive patient of this toxicity Those of be damaged, i.e., it is those of impaired to be subjected to liver function independently of the effect immediately of acetaminophen toxicity) in can be at lower dose Amount is lower to be occurred.This liver function it is impaired can by malnutritive or fasting, chronic condition (such as virus infection, such as virus infection, or Person's hepatic lesion as caused by chronic alcoholism) or acute condition (such as due to drug (drug i.e. except paracetamol) Liver function caused by effect or excessive Ethanol intake is impaired) cause.

Under any circumstance, it should be understood to the one skilled in the art that the treatment or prevention (such as prevention) of acetaminophen toxicity can be Know that the patient for having received (such as passing through intake) any paracetamol greater than therapeutic dose (or is needing cautious approach In the case of, it is believed that receive the object of (such as passing through intake) any paracetamol greater than therapeutic dose) it is middle with reference to this The standard therapeutic dose of any given patient known to the technical staff of field is (such as every 4 hours 1g in the adult of healthy weight, every The dosage of 24 hour period most 4g) it carries out.

It should be understood to the one skilled in the art that can be since application paracetamol itself be (such as in the form of paracetamol tablet, such as usually It is formulated for being administered orally or by those of venoclysis) or with the drug system comprising paracetamol and other active constituents The form of agent (such as preparation of the symptom designed for alleviating general flu and influenza) is applied paracetamol and is occurred Paracetamol over administration.

It should be understood to the one skilled in the art that treating or preventing acetaminophen toxicity as described herein should ideally use in paracetamol (starting) is carried out as early as possible after drug overdose, such as (or particularly, at 24 hours in 72 hours after over administration generation It is interior, such as in 12 hours, or more particularly, in 8 hours) it carries out.But it is treated using the compounds of this invention Not (needle in initial time period (such as first 24 hours, or more particularly, first 12 hours, such as first 8 hours) after over administration To paracetamol over administration) it can also work in the patient that is treated, it in this case can be in paracetamol medication After excess between 168 hours and 12 hours (such as between 72 hours and 12 hours, such as between 72 hours and 24 hours) It is treated in period.For example, can not treated (for paracetamol over administration) in first 8 hours after over administration Patient in treated using the compounds of this invention.

As described herein, the feature of acetaminophen toxicity can be acute hepatic failure.Therefore, there can be or face generation It is treated or prevented in patient's (such as facing the patient for generating acute hepatic failure risk) of acute hepatic failure risk as described herein Acetaminophen toxicity.

In addition, according to the second aspect of the invention, providing for treating or preventing urgency relevant to acetaminophen toxicity The compound N of property hepatic failure, the bis- -2- mercaptoethyl isophtalamides (NBMI) of N- or its pharmaceutically acceptable salt and/or Derivative.

In the alternative second aspect of the present invention, provide compound N, the bis- -2- mercaptoethyl isophtalamides of N- or Its pharmaceutically acceptable salt and/or derivative are for manufacturing treatment or prevention acute hepatic failure relevant to acetaminophen toxicity Drug purposes.

In further alternative second aspect of the invention, provide a kind of for treatment or prevention and acetaminophen toxicity The method of relevant acute hepatic failure, the method include to apply to patient with this need (patients of i.e. this treatment or prevention) With a effective amount of N, the bis- -2- mercaptoethyl isophtalamides of N- or its pharmaceutically acceptable salt and/or derivative.

In order to avoid query, about all embodiments described in first aspect present invention and special characteristic (and combinations thereof) It is suitable for the invention second aspect.

As used herein, refer to that " acute hepatic failure relevant to acetaminophen toxicity " is understood to refer to by flutterring hot breath Pain toxicity triggers the acute hepatic failure of (or resulting from), can be referred to as the acute hepatic failure as caused by acetaminophen toxicity.

It should be understood to the one skilled in the art that acute hepatic failure may be defined as generating hepatic dysfunction rapidly, it is characterised in that Generating blood coagulation disorders in the patient for not having pervious hepatopathy (such as without former known hepatopathy) (usually has greater than 1.5 International standardization ratio (INR)) and cerebral lesion (may be generally characterized as state of mind change).In addition, commonly known will lead to urgency The hepatic lesion of property hepatic failure can be related to the loss function of the liver cell of about 80% to about 90%.

It should be understood to the one skilled in the art that impaired (and similarly, reduction or abnormal) liver function refer to it is problematic sub-optimal Liver function is determined by clinician using technology well known by persons skilled in the art.For example, the common test being damaged for liver function (commonly referred to as liver function test (LFT)) includes alanine aminotransferase (ALT), asparagine present in measurement blood samples of patients Sour aminopherase (AST), alkaline phosphatase (ALP), γ glutamyl transferase (GGT), bilirubin or albuminised horizontal Those tests.Similarly, sub-optimal liver function can be studied by blood coagulation (such as by assessment prothrombin time (PT) or international standard Change ratio (INR)) it determines.Show correlated results of these impaired or abnormal tests of liver function for medical practitioner's (or ability Others skilled in the art in domain) for be well known.

It should be understood to the one skilled in the art that the treatment of acetaminophen toxicity or acute hepatic failure relevant to acetaminophen toxicity or pre- It is anti-can be combined with other treatments (i.e. drug and/or treatment method) for this purpose (i.e. as identical medical intervention one It applies part).

For example, due to taking in paracetamol and over administration, acetaminophen toxicity or malicious with paracetamol Property relevant acute hepatic failure treatment or prevention can with active carbon is administered orally or similar formulations combine.

In addition, this treatment or prevention can be with the one or more this field skills of application (such as be administered simultaneously or continuous administration) Art personnel are known to be used in treating or preventing the other of acetaminophen toxicity or acute hepatic failure relevant to acetaminophen toxicity Therapeutic agent (such as those of described herein below) combination.

As used herein, refer to that " continuous administration " can be related to apply each of a part as same medical intervention respectively Therapeutic agent (such as in 4 hours between each other, such as in 2 hours, or in especially 1 hour).

As described herein, the compounds of this invention can be in prevention acetaminophen toxicity or relevant to acetaminophen toxicity acute It is especially effective in terms of hepatic failure.

Therefore, the prevention of acetaminophen toxicity or acute hepatic failure relevant to acetaminophen toxicity is (as respectively at this Described in the first aspect and second aspect of invention) can with use paracetamol carry out treatment (such as slightly to moderate pain, hair The treatment of burning or other similar states, such as the paracetamol by applying therapeutically effective amount to patient with this need, it is described Treatment can carry out in the manner known to persons skilled in the art) combination, vice versa.

This combination (combine with paracetamol) is when (such as described herein to the patient more sensitive to acetaminophen toxicity Those of) and/or receive or need (it is 4g most to be greater than every 4 hours 1g, every 24 hour period than those of usually used Dosage) larger dose paracetamol treatment patient's application when may be particularly useful.

Pharmaceutical composition and dosage

It should be understood to the one skilled in the art that the compounds of this invention can allow whole body when being used for purposes as described herein and method The mode of absorption is applied, and the absorption can be occurred by several possible approaches；For example, the compounds of this invention can pharmaceutically connect The form of the pharmaceutical preparation comprising compound for the dosage form received by oral, intravenous or intra-arterial, intramuscular, skin, it is subcutaneous, Mucous membrane (such as sublingual or oral cavity), rectum, percutaneous, intranasal, transpulmonary (such as passing through sucking, tracheae or bronchus) or by appointing What its parenteral route is applied.Particularly, the compounds of this invention can be (such as defeated by vein by oral, rectum or vein Note) application.

The compounds of this invention is usually with the shape of one or more pharmaceutical preparations mixed with pharmaceutically acceptable excipient Formula application, the excipient can be selected suitably according to desired administration route and standard pharmaceutical practice.It is this pharmaceutically The excipient of receiving can be reactive compound chemically inert, and can not have harmful secondary make under conditions of use With or toxicity.This pharmaceutically acceptable excipient also may make the compounds of this invention release immediately (such as discharging rapidly) or Improvement release (such as sustained release).

Suitable pharmaceutical preparation is commercially available, or in the literature (referring to " pharmaceutical science and the reality of (for example) Remington Trample " (The Science and Practice of Pharmacy), the 19th edition, Mack Printing Company, guest's sunset method Buddhist nun Asia state Easton (nineteen ninety-five) and Martindale-The Complete DrugReference (the 35th edition), and wherein The file referred to) it is described, the relevant disclosure in all files is incorporated herein by reference.Otherwise, properly The preparation of preparation can be realized by technical staff using routine techniques non-inventive.In U.S. Patent application 2010/0227812 Also describe the suitable pharmaceutical preparation for being used together with the compounds of this invention.

Therefore, in the third aspect of the present invention, a kind of pharmaceutical composition is provided, it includes N, the bis- -2- mercaptoethyls of N- Isophtalamide or its pharmaceutically acceptable salt and/or derivative, and optionally one or more pharmaceutically acceptable Excipient, be used for:

(a) acetaminophen toxicity (as described herein) is treated or prevented；Or

(b) acute hepatic failure (as described herein) relevant to acetaminophen toxicity is treated or prevented.

It provides a method, is used in the alternative third aspect of the invention:

(a) acetaminophen toxicity (as described herein) is treated or prevented；Or

(b) acute hepatic failure (as described herein) relevant to acetaminophen toxicity is treated or prevented,

The method includes to apply a kind of a effective amount of pharmaceutical composition to patient with this need, it includes N, N- is bis-- 2- mercaptoethyl isophtalamide or its pharmaceutically acceptable salt and/or derivative, and optional one or more medicines Acceptable excipient on.

In order to avoid query, all embodiments and special characteristic described in first aspect present invention and second aspect (and combinations thereof) it is also applied for the third aspect of the present invention.

It should be understood to the one skilled in the art that referenced herein pharmaceutically acceptable excipient is pharmaceutically acceptable including referring to Adjuvant, diluent and/or carrier, the adjuvant, diluent and carrier are for those skilled in the art (as described herein) It will be known.

As described herein, pharmaceutical preparation technology well known by persons skilled in the art and material can be used be suitble to it is desired to It is prepared by the mode of medicine approach.Particularly, pharmaceutical preparation can be used oral preparation or intravenous formulations form (or preparation, Such as concentrate formulation, suitable for preparing intravenous formulations).

For example, when being intended for being administered orally, the pharmaceutical preparation comprising the compounds of this invention can be with tablet or oral The form of powder agent or solution provides, and respectively optionally includes suitable excipient, those skilled in the art can be used The technology preparation known.Similarly, when being intended for being injected intravenously (I.V.) administration, the pharmaceutical preparation comprising the compounds of this invention The form of the solution of intravenous administration can be suitble to provide, or as the solution of the suitable solution for preparing suitable intravenous administration It provides, technology well known by persons skilled in the art can be used to prepare.Similarly, when being intended for rectally, comprising this The pharmaceutical preparation of invention compound can be provided in the form of tablet (such as suppository) or powder agent or solution, respectively optionally Comprising suitable excipient, technology well known by persons skilled in the art can be used to prepare.

According to the severity of patient to be treated, administration route and situation (such as paracetamol excessive levels and its The severity of effect), the treatment effective dose (to the associated patient for having this to need) that the compounds of this invention can be different provides. Suitable dosage can be determined by technical staff using routine techniques, such as be determined by routine dose research on adjustment etc..

Similarly, the amount for the compounds of this invention for including in relevant pharmaceutical formulations can be according to desired the compounds of this invention agent Amount, the convenience prepared and administration route (it can then determine the availability that the compounds of this invention absorbs system) are come true It is fixed.

The suitable dose of the compounds of this invention may include dosage that range is about 0.05 to 300mg/kg (such as vein Administration), for example, about 0.5 to about 200mg/kg (for example, about 1 to about 100mg/kg, for example, about 5mg/kg or about 50mg/kg).

Particularly, this dosage can be within the period (such as 1 hour) of about 15 minutes, 1 hour or a few houres by quiet Arteries and veins administration, oral or rectal application (such as being administered by intravenous injection).In addition, this dosage can be repeated as needed, Such as in the form of periodic continuous infusion, the dosage of the infusion can be reduced constantly.

In order to avoid query, regardless of herein wherein using word " about ", such as in amount (such as the agent of active constituent Amount) in the case where use word " about ", it should be understood that this variable is approximation, like this can from numerical value change noted herein ± 10%, such as ± 5%, preferably ± 2% (such as ± 1%).

In order to avoid query, it should be understood to the one skilled in the art that the dosage of the compounds of this invention of (such as to mankind) application should be (and being more than the reasonable time range) is enough to generate desired treatment response or prevention effect in reasonable time range. For example, the compounds of this invention can be suitble to the form of (i.e. quickly or immediately) discharge active component rapidly to provide, such as with rapid The form of disintegration-type tablet provides, and technology well known by persons skilled in the art and material can be used to prepare for the tablet.

Under any circumstance, technical staff should be able to routinely determine the actual dose for being most suitable for individual patient.More than although The dosage is the demonstration of average case, but may exist certainly includes higher or lower dosage range individual cases, this Kind situation is included within the scope of the invention.

It is (such as logical that the application of the compounds of this invention can be continuous (such as by continuous venoclysis) or intermittent Cross bolus injection perhaps by periodically oral or rectal application tablet or solution for example by bolus injection or By periodically applying tablet or solution), or can be provided in the form of single dosage (such as by injecting or by applying With tablet or solution).Dosage form can also determine that vice versa by administration time and frequency.

Combination and more part kits

In purposes as described herein and method, the compounds of this invention can also be may be available with one or more in treatment liver Disease has shown that active ingredient combinations for treating hepatopathy.

Therefore, a kind of pharmaceutical preparation is provided in the fourth aspect of the present invention, it includes:

(a) bis- -2- mercaptoethyl isophtalamides of N, N- or its pharmaceutically acceptable salt and/or derivative；And

(b) one or more other therapeutic agents that can be used to treat or prevent acetaminophen toxicity,

And optional one or more pharmaceutically acceptable excipient.

In addition, in the fifth aspect of the invention, providing a kind of more part kits, it includes following components:

(A) a kind of pharmaceutical preparation, it includes N, bis- -2- mercaptoethyl isophtalamides of N- or its is pharmaceutically acceptable Salt and/or derivative, and optional one or more pharmaceutically acceptable excipient；And

(B) a kind of pharmaceutical preparation can be used to treat or prevent the other of acetaminophen toxicity and control it includes one or more Agent, and optional one or more pharmaceutically acceptable excipient are treated,

The component (A) and (B) are respectively to be suitble to the form applied together with another component to provide.

In order to avoid query, all embodiments and special characteristic described in first aspect present invention to the third aspect (and combinations thereof) it is also applied for the fourth aspect of the present invention and the 5th aspect.

It should be understood to the one skilled in the art that more part kits as described herein may include more than one preparation comprising appropriate Amount/dosage the compounds of this invention and/or more than one preparation comprising the one or more energy of appropriate amount/dosage Other therapeutic agents of acetaminophen toxicity are treated or prevented, enough so as to repeat administration.Preparation if there is more than one (includes Any reactive compound), these preparations can be identical, or the dosage in any compound, chemical composition And/or it can be different in terms of physical form.

As for more part kits as described herein, " with ... (administration in is applied together Conjunction with) " (and similar " with ... (administered in conjunction is applied together It with include) ") comprising the compounds of this invention and one or more other treatments that can treat or prevent acetaminophen toxicity The corresponding preparations of agent as same medical intervention a part of continuous administration, respectively apply or be administered simultaneously.

Therefore, term related to the present invention " with ... apply (administration in conjunction together With) " (and similar " with ... apply (administered in conjunction with) together ") it include two kinds of work Property ingredient (i.e. the compounds of this invention and one or more other therapeutic agents that can treat or prevent acetaminophen toxicity) it is same When application or in time close enough apply (optionally repeatedly), to make it possible to bring beneficial effect for patient, The beneficial effect treat it is conditions associated during than in the identical course for the treatment of in the case where lacking another component it is independent Apply the preparation of (optionally repeatedly) comprising the compounds of this invention or its pharmaceutically acceptable salt or comprising a kind of or more The preparation for other therapeutic agents that kind can treat or prevent acetaminophen toxicity is bigger.A kind of combine is treating or preventing correlation-like It can routinely be determined by technical staff during condition whether the conditions associated aspect for the treatment of or prevention can provide bigger beneficial effect.

In addition, in scene of the invention, term " with ... together " it include one of two kinds of preparations preparation or another kind Preparation can before applying another component, after, and/or while apply (optionally repeatedly).It is applied when in this case When, term " being administered simultaneously " and " with ... be administered simultaneously " include each individually dosed the compounds of this invention and one or more energy Enough treat or prevent in other therapeutic agents between each other 24 hours of acetaminophen toxicity (such as 12 hours, 6 hours, it is 3 small When, 2 hours, 1 hour, 45 minutes, 30 minutes, in 20 minutes or 10 minutes) application.

Therefore, the fifth aspect of the present invention additionally provides a kind of more part kits, it includes:

(I) one of the component as described in fifth aspect present invention (A) or (B)；And

(II) specification that the component is applied in combination with another component in described two components.

It can be used to treat or prevent suitable therapeutic agent (such as the component for fourth aspect present invention of acetaminophen toxicity (b) and the component of fifth aspect present invention (B) it is applied in combination, or with treatment or prevention described in first aspect present invention) packet Include antioxidant and chelating agent, such as vitamin-E, vitamin-D, cysteine, cystine, glutathione, lipoic acid paddy Guang Sweet peptide (GSH), dihydrolipoic acid (DLPA), lipoic acid (LPA), n-acetylcysteine (NAC), dimercaptopropane sulphonate salt (DMPS), dimercaptosuccinic acid (DMSA), ethylenediamine tetra-acetic acid (EDTA), Deferoxamine (DFO), Deferasirox, Deferiprone, Qu En Spit of fland, Beracilline, ammonium tetrathiomolybdate, four sulphur molybdic acid choline, and combinations thereof.

This special therapeutic agent that can be mentioned that includes n-acetylcysteine (NAC).

In the specific embodiment of fourth aspect present invention and the 5th aspect, pharmaceutical preparation or more part kits can bases It needs to be used for:

(a) acetaminophen toxicity (as defined herein) is treated or prevented；Or

(b) acute hepatic failure (as defined herein) relevant to acetaminophen toxicity is treated or prevented.

In fourth aspect present invention and the 5th aspect further embodiment, pharmaceutical preparation or more part kits can roots According to the method needed for following purpose:

(a) acetaminophen toxicity (as defined herein) is treated or prevented；Or

(b) acute hepatic failure (as defined herein) relevant to acetaminophen toxicity is treated or prevented,

Wherein this method may include to patient with this need apply therapeutically effective amount NBMI or its can pharmaceutically connect The salt and/or derivative received (such as pharmaceutical preparation or more part kits, it is effective to contain associated treatment as needed Amount).

Same as described herein, the compounds of this invention is in prevention acetaminophen toxicity or urgency relevant to acetaminophen toxicity Property hepatic failure in terms of may especially effectively, therefore can be used for paracetamol (such as in this paracetamol such as art technology Personnel become known for treatment slightly to moderate pain or fever when) be administered in combination, especially more sensitive to acetaminophen toxicity Patient's (as described herein) and/or receive or need than those of usually used (such as every 4 hours 1g, every 24 hour period The dosage of most 4g) larger dose those of the treatment of paracetamol patient in.

Therefore, a kind of pharmaceutical preparation is provided in the sixth aspect of the present invention, it includes:

(b) paracetamol,

And optional one or more pharmaceutically acceptable excipient.

In addition, providing a kind of more part kits in the seventh aspect of the present invention, it includes following components:

(B) a kind of pharmaceutical preparation, it includes paracetamols, and optional one or more pharmaceutically acceptable figurations Agent,

In order to avoid query, in terms of the present invention the first to the 5th the embodiment described and special characteristic (and combinations thereof) It is also applied for the sixth aspect of the present invention and the 7th aspect.

The seventh aspect of the present invention additionally provides a kind of more part kits, it includes:

(I) one of the component as described in seventh aspect present invention (A) or (B)；And

Particularly, the pharmaceutical preparation as described in sixth aspect present invention and the multi-section as described in seventh aspect present invention point examination Agent box can be used for treating following disease (or can be used for method) for treating following disease:

Slightly to moderate pain or fever, especially to the more sensitive patient (as described herein) of acetaminophen toxicity And/or

Patient and/or receiving with more serious pain or fever or need than usually using those of it is (such as big In the dosage of every 4 hours about 1g, at most every 24 hour period about 4g；Such as it is up to about 8g within any 24 hour period, such as It is up to about 16g, even as high as about 24g or up to about 32g) in the patient of the treatment of the paracetamol of larger dose.

The suitable dose for the other therapeutic agents (such as NAC) being mentioned above will be known to those skilled in the art , and those of listed including being directed to related drug in relevant medical literature, such as Martindale-The Complete It those of is listed in Drug Reference (the 35th edition) and the file being mentioned above, in the correlation in all files is open Appearance is incorporated herein by reference.

The preparation of compound and preparation

The compounds of this invention can be commercially available, or technology well known by persons skilled in the art can be used to prepare, example Technology those of described in publication as mentioned herein.For example, NBMI can be according to U.S. Patent number US6, in 586,600B2 The step preparation, content (the step of described in the example especially wherein provided) are incorporated herein by reference.

As described herein, pharmaceutical preparation is (including as according to the fourth aspect of the invention containing more than one active constituents Those) it technology well known by persons skilled in the art can be used to prepare.Similarly, more part kit (such as fifth aspect present invention It is described) it technology well known by persons skilled in the art can be used to prepare.

Further aspect according to the present invention provides:

A method of the pharmaceutical preparation as described in terms of preparing such as fourth aspect present invention and the 6th, it includes such as this hairs It is described in terms of bright fourth aspect and the 6th to be combined into component (a) and (b) mixture (being combined into identical preparation), and optionally Ground is in conjunction with one or more pharmaceutically acceptable excipient；And

A method of more part kits as described in terms of preparing such as fifth aspect present invention and the 7th, it includes will Component (A) and (B) as described in terms of fifth aspect present invention and the 7th combine.

In order to avoid query, by each component in terms of " in conjunction with " includes such as fifth aspect present invention and the 7th mutually as described in it is more The component (A) of part kit and (B) can be with:

(i.e. independently from each other) is provided as isolated preparation, is then put together for being combined with each other for combining Treatment；Or

It is packaged as the separation component of " combination packet " and the separation component as " combination packet " provides, for being combined with each other use In combined therapy.

When be used for purposes as described herein and method when, the compounds of this invention acetaminophen toxicity or with paracetamol poison Property relevant acute hepatic failure treatment or prevention in can have the advantage that and similar treatment well known in the prior art or pre- Anti- measure is compared may be for doctor and/or patient are more convenient, more effective, toxicity is lower, have broader field of activity, effect It is higher, generate less side effect or can have other useful pharmacological characteristics.

Without wishing to be bound by theory, it is believed that the compounds of this invention is metabolized with the ratio of 1:2 and acetaminophen toxicity Object (NAPQI) combines in vitro and the unexpected activity of (importantly) Binding in vivo aspect allows effectively to block it unexpectedly The method of hepatic injury effect, to be prevented it (if early stage applies) or treatment (if this damage is made by providing And have begun occur after apply) effective ways mitigate paracetamol toxicity.

Particularly, it is believed that NBMI can effectively Binding in vivo NAPQI, to provide the body of directly blocking acetaminophen toxicity Interior effect (rather than working as in the case where the medicament as NAC as glutathione precursor) has efficacious prescriptions Method.

Detailed description of the invention

Fig. 1 shows results of in vitro studies, wherein the NBMI that display NAPQI is stored in the activation of calcium channel TRPA1 Inhibit.

Fig. 2 a and Fig. 2 b show the clinical evidence of conceptual approach as a result, it shows that NBMI is likely to tie with NAPQI in vivo It closes.

Effect of the NBMI to acetaminophen toxicity in the mice study of paracetamol is administered orally in Fig. 3 display.

Fig. 4, which is shown, applies effect of the NBMI to acetaminophen toxicity in the ALT chemical examination of paracetamol by intraperitoneal injection.

Fig. 5, which is shown, applies effect of the NBMI to acetaminophen toxicity in the AST chemical examination of paracetamol by intraperitoneal injection.

Fig. 6 is shown in the paracetamol of intraperitoneal application 200mg/kg and the synchronous NBMI or load that 680mg/kg is administered orally The level (unit/L) of liver enzyme ALT and AST after body 24 hours in mouse.* and * * * marks the height for showing statistical significance Degree.

Specific embodiment

The present invention is further illustrated by following instance, but is not limited.

Example 1- in vitro study shows NBMI in conjunction with NAPQI

Calcium channel TRPA 1 is activated by NAPQI.This activation can be imaged by ratio formula calcium and be determined.

The HEK293 cell of expression people TRPA1 uses 7 μM of NAPQI and calcium fluorogen FURAII to cultivate in advance.One experiment It is carried out in the presence of 4 μM of NBMI, another experiment carries out in the presence of 4 μM of NAC.

In the presence of no NBMI or NAC, NAPQI causes about 55% receptor activation.As shown in Figure 1,4 μM The presence of NBMI almost inhibits the activation of receptor, and the presence of 4 μM of NAC then only generates part and inhibits.

This also indicates that, per molecule NBMI with the relationship of 1:2 in conjunction with two molecule NAPQI, and NAC then with the relationship of 1:1 with Unimolecule NAPQI is combined.

The clinical evidence of example 2- conceptual approach

Experimental clinic is carried out under three circumstances in Lund Hospital Clinical Trial Unit to grind Study carefully.In each case, standard non-toxic therapeutic agent was taken at T=0 hours in the case where applying before or not applying NBMI The 1g paracetamol of amount, and the venous blood samples liquid during 8 hours.The result of this experiment is summarized in Fig. 2 a and 2b.

When starting, higher three lines show the concentration (intake) of paracetamol on the left of Fig. 2 a, and each curve is almost the same (they should be so).After 6 hours, no paracetamol residual is all decomposed.

Some paracetamols of 5-10% resolve into toxic metabolites NAPQI in liver.In order to release toxicity, gluathione Peptide is in connection, forms metabolin glutamy amido-paracetamol, is then changed into non-toxic metabolin cysteinyl-- Paracetamol (Cys- paracetamol), can measure in blood, be shown as the line labeled as " mediator " in figure 2b.

The two lines of NBMI concentration are marked to show that Cys- flutters heat when taking NBMI before applying paracetamol in Fig. 2 b The concentration for ceasing pain is lower, is shown in front of application paracetamol and takes within 1 hour the NBMI of 600mg and drop area under a curve (AUC) Low 23%, and 2 hours NBMI for taking 1,200mg are reduced by 73% before applying paracetamol.

These results indicate that NBMI is in the presence of glutathione in vivo in conjunction with NAPQI.

General information-example 3 to 5

In normal mouse, liver enzyme alanine aminotransferase (ALT) level is about 36-40 unit/L, and liver enzyme lucid asparagus Propylhomoserin transaminase (AST) level is about 90 units/L.Under the toxicity dose of paracetamol, increase toxic metabolites NAPQI's Level can consume the glutathione in liver, so as to cause oxidative stress, and ALT and/or AST level be caused to increase above 1,000 unit/L, this is considered as toxicity in the mankind.AST:ALT ratio in the mankind can also be related；Equal to or less than 1 Value be considered showing with toxicity.

The mice study (paracetamol is administered orally) of 3-paracetamol of example poisoning

Researching and designing

The mouse of six (6) overnight fasting respectively receives the paracetamol of 700mg/kg toxicity dose (to acetyl by oral administration Amino phenols).After 20 minutes, half mouse (3) only applies mediator (carboxymethyl cellulose of (w/v), 300-600 0.5% in water Centipoise), half mouse (3) receives the NBMI of 100mg/kg by oral administration (NBMI is dissolved in CMC as described below).48 hours it All mouse are put to death using anesthesia (if necessary) afterwards or earlier.

As a result

Mouse needs to put to death at 17 hours, because the control mice situation of poisoning (i.e. paracetamol poisoning) is very poor.In Fig. 3 Summarize each as a result, it shows that liver enzyme ALT is horizontal in terms of unit/L mouse.

Intermediate value ALT level in control mice is 13,680 units/L, than normal level (36 units/L) Gao great Yue 380 Times, it is 13 times of human toxicity's horizontal (1,000 unit/L).

Intermediate value ALT level through NBMI processing group is 624 units/L, therefore lower than intoxicated animals intermediate value about 95%, and Infrahuman toxic level.

The mice study (intraperitoneal application paracetamol) of example 4- paracetamol poisoning

Researching and designing

(I.P.) receives the paracetamol (paracetamol of 300mg/kg toxicity dose in the mouse peritoneal of six (6)； APAP).After 30 minutes, two (2) mouse only applies carrier, and two (2) only receive the NAC of 1200mg/kg, two (2) by oral administration Only receive the NBMI of 200mg/kg by oral administration.Mouse is put to death at 24 hours.

ALT result

ALT result of laboratory test is shown in FIG. 4.As can be seen that poisoning mice has about 8,000 unit/L ALT is horizontal. ALT is maintained at 55 average level by application NAC.ALT is maintained at 984 average level by the NBMI of application 200mg/kg, Toxic level lower than 1,000.

AST result

AST result of laboratory test is shown in FIG. 5.Poisoning mice has about 6,000 units/L AST horizontal.Applying NAC will AST is maintained at 180.ALT level is maintained at 600 by the NBMI of application 200mg/kg.

In mouse (intraperitoneal application paracetamol) that example 5- is poisoned in paracetamol application NMBI relative to control (only Use carrier) effect

The paracetamol of fasted mice intraperitoneal injection 200mg/kg, and synchronous oral administration (i) CMC carrier is (medium viscous The sanlose of degree) in 680mg/kg NBMI, or (ii) individual CMC carrier；Administered volume is 5 μ L/ gram Weight.NBMI dosage is selected as it and shows the dosage that can be provided with 4.5-9mg/kg in the mankind in toxicity research on the 28th (not showing the dosage of adverse events relevant to drug in clinical trial) is similar to expose to the open air.By mouse after administration 24 hours It puts to death, then measures the level of liver enzyme AST and ALT.

In the group handled through NBMI, 11 (11) mouse is handled.One result be classified as outlier (according to The test of Grubbs outlier, and the haemocylolysis due to observing).The average value of the result obtained from remaining mouse is aobvious Show:

AST (unit/L) -753 (value=0.00204 P-, as calculated by Excel)

ALT (unit/L) -952 (value=0.00006 P-, as calculated by Excel)

AST/ALT ratio -2.1 (value=0.00068 P-, as calculated by Excel)

In the group that carrier is used only, 13 mouse are handled.The average value of result obtained is shown:

AST (unit/L) -8507

ALT (unit/L) -14511

AST/ALT ratio -0.5

Each result is summarized in Fig. 6.

Claims

1. bis- -2- mercaptoethyl the isophtalamides (NBMI) of a kind of N, N- or its pharmaceutically acceptable salt and/or derivative, It is used to treat or prevent acetaminophen toxicity.

2. the purposes of the bis- -2- mercaptoethyl isophtalamides of a kind of N, N- or its pharmaceutically acceptable salt and/or derivative, It is used to manufacture the drug to treat or prevent acetaminophen toxicity.

3. a kind of method for treating or preventing acetaminophen toxicity, the method includes effective to patient in need application Bis- -2- mercaptoethyl the isophtalamides of the N of amount, N- or its pharmaceutically acceptable salt and/or derivative.

4. bis- -2- mercaptoethyl the isophtalamides of a kind of N, N- or its pharmaceutically acceptable salt and/or derivative, are used for Treat or prevent acute hepatic failure relevant to acetaminophen toxicity.

5. the purposes of the bis- -2- mercaptoethyl isophtalamides of a kind of N, N- or its pharmaceutically acceptable salt and/or derivative, It is used to manufacture the drug to treat or prevent acute hepatic failure relevant to acetaminophen toxicity.

6. a kind of method for treating or preventing acute hepatic failure relevant to acetaminophen toxicity, the method includes to having The patient that needs apply a effective amount of N, the bis- -2- mercaptoethyl isophtalamides of N- or its pharmaceutically acceptable salt and/or Derivative.

7. a kind of pharmaceutical preparation, it includes:

And optional one or more pharmaceutically acceptable excipient.

8. a kind of more part kits, it includes following components:

(A) pharmaceutical preparation, it includes N, the bis- -2- mercaptoethyl isophtalamides of N- or its pharmaceutically acceptable salt and/ Or derivative and optional one or more pharmaceutically acceptable excipient；And

(B) pharmaceutical preparation, it includes it is one or more can be used in treat or prevent acetaminophen toxicity other therapeutic agents, with And optional one or more pharmaceutically acceptable excipient,

The component (A) and (B) are respectively to be suitble to the form applied in conjunction with another component to provide.

9. a kind of pharmaceutical preparation, it includes:

(b) paracetamol,

And optional one or more pharmaceutically acceptable excipient.

10. a kind of more part kits, it includes following components:

(A) pharmaceutical preparation, it includes N, the bis- -2- mercaptoethyl isophtalamides of N- or its pharmaceutically acceptable salt and/or Derivative, and optional one or more pharmaceutically acceptable excipient；And

(B) pharmaceutical preparation, it includes paracetamol and optional one or more pharmaceutically acceptable excipient,

11. a kind of reference example substantially as described herein for use compound, purposes, method, the drug system for using Agent, combination product or more part kits.